Table 1.
Summary of therapy resistance mechanisms driven by tumor microenvironment in pancreatic cancer.
| Cell Type | Therapy | Resistance Inducer |
Detailed Mechanism | Reference |
|---|---|---|---|---|
| PSCs | chemotherapy (gemcitabine) | Collagen I | Promote proliferation by MAPK pathway activation and chromatin remodeling | [62,63] |
| Periostin | Induce ECM molecules, including collagen I | [60,61] | ||
| fibronectin | Promote proliferation by MAPK pathway activation | [64] | ||
| IGF1, IGF2 | Activate IGFR-PI3K-AKT pathway | [65] | ||
| LIF | Activate Wnt and Hippo signaling pathways and induce EMT | [66] | ||
| HGF | Activate c-Met-PI3K-Akt pathway and induce EMT | [67] | ||
| CYR61 | Downregulate nucleoside transporters ENT1 and CNT3 | [68] | ||
| Deoxycytidine | Compete with gemcitabine for deoxycytidine kinase-mediated phosphorylation | [69] | ||
| immunotherapy | CXCL12 | Chemoattract CD8+ T cells via CXCL12-CXCR4 axis to sequester them in the panstromal compartment | [70] | |
| Galectin-1 | Induce T cell apoptosis and Th2 differentiation | [71] | ||
| IL-6 | Promote MDSC differentiation via STAT3 activation and suppress T cell proliferation | [72] | ||
| CAFs | chemotherapy (gemcitabine) | 5′-nucleotidases | Entrap active gemcitabine intracellularly via downregulation of Nt5c1A, Nt5c3 | [75] |
| Exosomes | Deliver SNAI1 and miR-146a to tumor cells via exosomes | [76] | ||
| circFARP1 | Enhance LIF expression and secretion | [77] | ||
| TGF-β | Upregulate ATF4 in tumor cells to activate ABCC1 expression | [78] | ||
| SDF-1 | Form a reciprocal feedback loop with tumor cells via SDF-1/SATB-1 axis | [79] | ||
| IL-6 | Activate JAK-STAT3 signaling pathway | [80] | ||
| CXCL12 | Bind to CXCR4 to activate FAK, AKT, and ERK pathways | [81] | ||
| chemotherapy (oxaliplatin) | IL-8 | Upregulate UPK1A-AS1 to facilitate DNA repair | [82] | |
| chemotherapy (etoposide) | NO | Elevate IL-1β production in tumor cells | [83] | |
| targeted therapy (EGFRi erlotinib) | NRG-1 | Activate ERBB3-AKT signaling pathway | [84,85] | |
| immunotherapy | ECM | Form a physical barrier to impede T cell-tumor cell contact | [86] | |
| ROS | Induce M2 TAM polarization | [87] | ||
| / | Suppress immunogenic activities | [88] | ||
| CXCL12 | Exclude T cells from tumor region by binding to CXCR4 | [89] | ||
| PGE2 | Induce expression of immune checkpoints on CD4+ and CD8+ T cells | [90] | ||
| TSLP | Induce Th2 cell polarization through dendritic cell conditioning | [41] | ||
| targeted therapy (GOT2i) | Pyruvate | Provide tumor cells with pyruvate to maintain redox balance | [91,92] | |
| TAMs | chemotherapy (gemcitabine) | Deoxycytidine | Interfere the uptake and metabolism of gemcitabine | [93] |
| Cytidine deaminase | Elevate cytidine deaminase expression in tumor cells to inactivate gemcitabine | [94] | ||
| targeted therapy (KRASi) | TGFβ | Activate canonical SMAD3/4 pathway and promote EMT | [95] | |
| immunotherapy | Granulin | Induce fibrosis to prevent T cell infiltration | [96] | |
| Mincle | Ligate to SAP130 expressed by tumor cells to suppress cancer immunity | [97] | ||
| RIP1 | Regulate M2 TAM polarization | [98] | ||
| radiotherapy, immunotherapy | / | n/a | [99,100] | |
| TANs | chemotherapy (gemcitabine) | IL-6 | Activate JAK-STAT3 signaling pathway | [80] |
| immunotherapy | NETs | Cause tumor CD8+ T cell inactivation and spatial exclusion | [101] | |
| chemotherapy (FOLFIRINOX, gemcitabine, nab-paclitaxel), radiotherapy, immunotherapy | / | n/a | [102,103,104,105,106,107] |
EGFRi, EGFR inhibitor; KRASi, KRAS inhibitor; n/a, not addressed.